Quinolone caroxylic acids are known to be effective antibacterial agents. Some of these compounds, however, have low solubility at neutral pH values, a characteristic which can adversely affect their suitability for parenteral administration to patients. Moreover, a common side-effect of intravenous administration is discomfort due to venous irritation. Hemolysis is a further undesirable side-effect which may in some instances be observed upon intravenous administration of quinolone carboxylic acids.
One especially effective quinolone carboxylic acid antibacterial compound is temafloxacin, a quinolone 3-carboxylic acid represented by the formula: ##STR1## and having the chemical name 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-(3-methyl-l-piperazinyl)-4-o xo-3-quinoline carboxylic acid. Temafloxacin is disclosed in U.S. Pat. No. 4,730,000, issued to Chu.
Temafloxacin and its derivatives and salts have antibacterial activity, and are known to be useful for combating bacterial infections in warm-blooded animals. The solubility of temafloxacin base in water, however, is less than 0.5 mg/ml. Acidic or basic salts can be prepared at extreme pH values, as for example less than pH 4 for acid salts or greater than pH 10 for basic salts. Unfortunately, such solutions may be unsuitable for parenteral formulations due to their non-physiological pH, which upon injection is believed to contribute to the above-mentioned venous irritation. Moreover, these solutions are relatively physically unstable at high concentrations, as for example those greater than 10 mg/ml.
The preparation of certain parenterally administrable compositions of quinolone carboxylic acids has been reported by Preiss et al. in European Patent Application No. 287 926 and by Grohe et al. in U.S. Pat. Nos. 4,808,583 and 4,705,789. The application of Preiss et al. discloses the preparation of highly purified quinolone carboxylic acids said to be suitable for administration in parenteral solution. The highly purified quinolone carboxylic acid is prepared by dissolving the quinolone, or a salt thereof, with an acid, preferably in the presence of activated charcoal. The mixture is maintained for 0.15 to 150 hours, after which it is filtered and the quinolone carboxylic acid precipitated by addition of a basic reagent. The precipitated quinolone carboxylic acid is then dissolved for parenteral use. This method reportedly produces stable pharmacological solutions of quinolone carboxylic acids such as ciprofloxacin.
The above U.S. patents of Grohe et al. disclose lactic acid salts of quinolone carboxylic acids, as well as acid addition salts, that are said to be stable in solution at pH values of between 2.5 and 7 but more reliably at pH values of between 3.5 and 4.5. Quinolone carboxylic acids, or salts thereof, are dissolved in lactic acid, followed by the adjustment of concentration with water, or titration of pH with sodium hydroxide or acids such as methanesulfonic acid or propionic acid.
However, higher-concentration solutions of quinolone carboxylic acids which are chemically and physically stable near physiological pH, and which are suitable for parenteral administration to human or veterinary patients, have not been reported in the literature. Also, many formulations of quinolone carboxylic acids have been observed to produce hemolysis upon infusion. There consequently remains a need for stable compositions of quinolone carboxylic acids which do not produce the venous irritation and/or hemolysis frequently observed when known compositions are administered intravenously.